Research in drug delivery technology continues to escalate as innovative delivery systems are found in many cases to offer advantages over conventional drug formulations. For example, alternate drug delivery systems have been shown to provide therapeutic advantages by increasing efficacy and safety, while reducing side effects. Many of these systems offer usage benefits to the patient, including more convenient dosage forms and administration schedules. In addition, alternate delivery systems enable new indications for approved drugs, including generics. Further, the development of new drug delivery systems has expedited approval and widespread use of many new drugs in development. Accordingly, the worldwide market for alternate drug delivery systems has more than doubled over the past five years to approximately $6 billion, and annual growth rates averaging 30% to 40% have been projected for the next several years. Examples of FDA-approved drug delivery systems include polymers, osmotics, liposomes, nasal and transdermal formulations, aerosols and resins. Emerging delivery systems include gels, foams, microparticles, red blood cells and prodrugs. In addition, many device technologies are being developed to improve the efficiency and/or convenience of drug administration, including controlled infusion devices (e.g., for patient-controlled analgesia), metered-dose inhalers and implantable pumps.
Alternative drug delivery systems are particularly important for emerging biopharmaceuticals, which represent the most active area of therapeutic market growth and product innovation. The vast majority of approved and pending biopharmaceuticals are recombinant peptides and proteins that cannot be efficiently administered orally and may be either ineffective, preclusively inconvenient or otherwise unacceptable as injectibles. The commercial potential of such compounds and the rate of market development will depend in large part on improved drug delivery systems.
Drug delivery systems are defined herein as dosage forms (comprising one or more drugs) that provide increased control over drug concentration and/or duration of action either systemically or at anatomically or pathophysiologically defined sites. Primary approaches being developed include controlled release formulations, local delivery of drugs in biocompatible matrices, targeted delivery using receptor- or membrane-directed agents and prodrug compositions that remain therapeutically inactive until converted to active drug in vivo.
Local delivery is intended to provide a therapeutically effective concentration of drug at the desired site of action for a clinically appropriate period of time without the toxicity and side effects that might result from systemic administration. Representative indications include periodontal diseases, ophthalmic infections and a variety of cancers. Approaches in development include bioerodable polymers, gels, foams, microparticles, microvesicles, proteinaceous matrices and implantable pumps. Most local delivery approaches include a built-in sustained release mechanism to provide prolonged action following administration. However, local delivery requires convenient access to the site of interest, preferably either by noninvasive techniques or an otherwise-indicated surgical procedure. Further, local delivery fails to provide diffuse or systemic protection, as may be important in metastatic disease, fulminant infections or other conditions prone to migration from a primary site.
Controlled release formulations are designed to maintain drug concentrations within the therapeutic range without the dramatic peak-to-trough variability that occurs with conventional administration. Elimination of peak levels improves drug safety by reducing toxicity and side effects. Avoiding troughs obviates the risk of symptoms being unmasked during periods of subtherapeutic drug levels. Most controlled release technologies incorporate a sustained release mechanism that provides for prolonged action of drugs with short half-lives, thereby increasing dosage intervals, ease of use and patient compliance. Prodrugs represent a special category of controlled release formulations, wherein the drug composition is inactive as administered, but is converted to active form in vivo through exposure to a particular physiologic environment or metabolic process. Controlled release has been successfully used to increase the bioavailability of orally administered drugs, to minimize fluctuations in systemic drug levels, to provide coarse control over biodistribution and to increase the half-life of drugs administered both locally and systemically. A major shortcoming of controlled release formulations, however, is the limited extent to which drug disposition can be practically controlled through nonselective mechanisms.
Drug targeting refers to preferential delivery of therapeutic agents to clinically relevant organs, tissues, cells or receptors. Preferential delivery is achieved either through specific molecular targeting agents or through methods that alter the physicochemical properties of a drug so as to alter its pharmacokinetic properties and biodistribution. Specific molecular targeting agents such as monoclonal antibodies, lectins, peptides and specific sugars selectively bind to pathophysiologic receptors, thereby bringing a conjugated drug into close proximity with its site of action. Altering the physicochemical properties of a drug or drug-carrier complex can nonselectively influence drug distribution through effects on binding and uptake by different cell types and transport across physiologic barriers such as the gastric mucosa, skin, capillary membrane and blood-brain barrier. Examples of targeting approaches include immunoconjugates and monoclonal antibody-modified liposomes designed to specifically bind clinically significant receptors or disease markers and drugs conjugated to carriers or delivered in vehicles that enhance membrane permeability. However, such therapeutic conjugates have yet to be widely accepted. Aside from technical challenges related to tissue penetration, stability and immunogenicity, a problem with immunoconjugates and related targeting strategies is that they do not increase the percent of administered drug that gains access to the desired site of action. Affinity-based targeting agents increase the probability that a drug near its site of action will exert an effect, but they fail to increase the percentage of administered drug that reaches the desired site. Accordingly, these agents do not provide a mechanism to sequester or concentrate drug at the desired site of action. Affinity-based delivery vehicles in development provide only for partitioning of drug conjugates between bound (e.g., to targeted receptors) and free (e.g., in extracellular fluid) phases, which partitioning is directly dependent on the bulk concentration of drug conjugate. The efficiency of delivery is therefore limited both by the affinity of the targeting agent for its receptor and by the percentage of administered drug that distributes to therapeutically relevant sites. In general, treatment of localized conditions such as cancers, infections and vascular occlusions by systemic administration of therapeutic immunoconjugates is highly inefficient. Only a small fraction (<1%) of administered conjugate interacts with targeted receptors, the remainder being metabolized and excreted.
Accordingly, there is a growing need for drug delivery systems that provide greater efficiency, safety, duration of action and convenience than current drug targeting methods.